The role of miRNAs in hormone signaling

Deo Prakash Pandey, Marcela Bennesch & Didier Picard

Steroid receptors belong to a family of transcription factors whose transcriptional activities are regulated by their respective hormonal ligands. Mechanisms that affect the receptor levels and/or the expression of their regulators and target genes can be expected to shape hormonal responses. miRNAs are newly recognized regulatory molecules that act at all these levels. We have done a comprehensive survey of miRNAs that might regulate the expression of the estrogen receptor α (ERα), and identified several that affect its levels. They target the long 3′ UTR of the ERα mRNA to reduce its stability and/or translation. Amongst the identified miRNAs, miR-22 inhibits ERα expression and thereby ERα functions. Therefore, in breast cancer cells that depend on ERα function for proliferation, miR-22 can be considered a tumor suppressor. Intriguingly, other miRNAs appear to increase ERα expression. While we are currently investigating the mechanism of this unusual effect, increased ERα levels may explain why some of these miRNAs have previously been associated with more aggressive breast cancers. Additional complexity stems from the facts that miR-22 might also regulate the expression of other nuclear receptors and that the expression of miRNAs themselves can be affected by steroid hormones. Thus, miRNAs play a multifaceted role in fine-tuning steroid hormone responses at multiple different levels.